Bioactive small molecules are powerful tools used to evaluate protein function under physiological and pathological conditions. Over recent decades, utilization of a variety of biologically active small molecules in basic research and clinical applications has provided tremendous benefits in understanding the molecular mechanisms of biology and accelerating drug development. This review focuses on recent advances in the identification of new small molecules and their target proteins for exploring angiogenesis at the molecular level. In particular, we focus on the oxygen-sensing role of ubiquinol-cytochrome c reductase binding protein (UQCRB) of mitochondrial Complex III through identification of the protein target and the mode of action of a natural small molecule, terpestacin. The positive feedback approach of chemistry and biology provides a new way to explore functional roles of proteins and to translate this information into practical applications.